1. Field of the Invention
The present invention relates to a process for the preparation of a solid, orally administrable pharmaceutical composition, comprising 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)-phenyl]-1,3-oxanzolidin-5-yl}-methyl)-2-thiophenecarboxamide in hydrophilized form, and its use for the prophylaxis and/or treatment of diseases.
2. Description of Related Art Including Information Disclosed Under 37 CFR 1.97 and 1.98.
5-Chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)-phenyl]-1,3-oxazolidin-5-yl}-methyl-2-thiophenecarboxamide (I) is a low molecular weight, orally administrable inhibitor of blood clotting factor Xa, which can be employed for the prophylaxis and/or treatment of various thromboembolic diseases (for this see WO-A 01/47919, whose disclosure is hereby included by way of reference). If, below, the discussion is of the active compound (I), all modifications of 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)-phenyl]-1,3-oxazolidin-5-yl}-methyl)-2-thiophenecarboxamide (I), and the respective hydrates are additionally included.
The active compound (I) has a relatively poor water solubility (about 7 mg/l). As a result of this, difficulties with the oral bioavailability and an increased biological variability of the absorption rate can result.
To increase the oral bioavailability, various concepts have been described in the past:
Thus, solutions of active compounds are frequently used which can be filled, for example, into soft gelatine capsules. On account of the poor solubility of the active compound (I) in the solvents used for this purpose, this option is not applicable, however, in the present case, since, in the necessary dose strength, capsule sizes would result which are no longer swallowable.
An alternative process is the amorphization of the active compound. Here, the solution method proves problematical, since the active compound (I) is also poorly soluble in pharmaceutically acceptable solvents such as ethanol or acetone. Amorphization of the active compound by means of the fusion method is also disadvantageous because of the high melting point of the active compound (about 230° C.), since an undesirably high proportion of breakdown components is formed during the preparation.
Furthermore, a process for the hydrophilization of hydrophobic active compounds as exemplified by hexobarbital and phenytoin has been described (Lerk, Lagas, Fell, Nauta, Journal of Pharmaceutical Sciences Vol. 67, No. 7, July 1978, 935-939: “Effect of Hydrophilization of Hydrophobic Drugs on Release Rate from Capsules”; Lerk, Lagas, Lie-A-Huen, Broersma, Zuurman, Journal of Pharmaceutical Sciences Vol. 68, No. 5, May 1979, 634-638: “In Vitro and In Vivo Availability of Hydrophilized Phenytoin from Capsules”). The active compound particles are blended here in a mixer with a methyl- or hydroxyethylcellulose solution with extensive avoidance of an agglomeration step and then dried. The active compound thus obtained is subsequently filled into hard gelatine capsules without further treatment.